Approximately 220,000 new prostate cancer cases are projected for the United States in 2003. Prostate cancer is usually an indolent disease, but 25%-30% of the tumors behave aggressively, resulting in almost 30,000 deaths. Large ethnic and geographic differences have been observed in the incidence of the disease, and environmental and genetic risk factors are thought to be involved. Migrant studies support the contribution of environmental factors and lifestyle. The adoption of a Western-type, high meat and high animal fat diet has been found to strongly increase the risk for prostate cancer. Other observations point to the role of genetic susceptibility factors in human prostate cancer. A study of twins estimated that 42% of the observed prostate cancers were associated with inherited genetic risk factors. Prostate cancer biology appears to be different in African-Americans when compared with Caucasians. The highest incidence worldwide is found among African-Americans. Some data indicate that an earlier onset and a more rapid progression of the disease in African-Americans contribute to the difference in mortality between the two ethnic groups. Prostate tumors are mainly adenocarcinoma, and are categorized by a Gleason score into low- and high-grade tumors. The frequency of latent, low-grade carcinomas appears to be similar in low-risk and high-risk populations. In contrast, larger carcinomas are more common in high-risk populations, and the frequency correlates with the incidence rate of clinical disease. The data indicate that genetic and/or environmental factors modulate the progression from a small, microscopic carcinoma into a large carcinoma, and that tumor progression is the critical step that defines the strong ethnic differences in prostate cancer risk and mortality. Prostatic intraepithelial neoplasia is considered the most likely precursor of invasive adenocarcinoma and frequently arises in inflamed areas. Acute and chronic inflammation is commonly observed in prostate biopsies and will lead to atrophic acini and hyperplasia. The inflammation-carcinoma sequence is a significant mechanism in prostatic carcinogenesis. Focal prostatic glandular atrophy and post-atrophic hyperplasia are potential precursors of adenocarcinoma and occur in close association with chronic inflammation. Chronic inflammation has been linked to the development of carcinoma in liver and colon, and may also lead to the development of precancerous and malignant lesions of the prostate. Our group has initiated several prostate cancer projects. We are particularly interested in identifying the factors that cause prostate cancer in African-Americans. The mortality rate is 2- to 3-fold higher for African-Americans than Caucasians, although the age-adjusted African-American to Caucasian cancer incidence ratio is only about 1.6. We developed a protocol and questionnaire for a prospective prostate cancer case-control study in the greater Baltimore area. The study will investigate genetic and dietary risk factors of prostate cancer in a cohort of African-American and Caucasian men. The objective is to identify the factors that drive the aggressive nature of prostate cancer in African-Americans. The protocol has been submitted to the NCI IRB for approval. In collaboration with Dr. Neil Caporaso (DCEG), we have received serum and DNA samples, and fresh-frozen tumor biopsies, from a prostate cancer case-control cohort. We will genotype the DNA to investigate the association between allele variants in genes of the angiogenesis and inflammation pathways, and the risk for developing prostate cancer. We have also requested fresh-frozen tumor specimens with a limited patient profile, such as race, age, tumor stage, survival, and family history of prostate cancer, from the NCI Prostate Tissue Resource. One objective is to study gene and protein expression profiles in prostate cancer that are associated with cancer progression and poor survival. We hypothesize that the progression of the disease, and the invasion of normal surrounding tissue, is driven by gene products of tumor and stromal cells. We will use laser-captured microdissection to separate tumor from normal tissue, and to determine the molecular profiles that separate 1) high-stage from low-stage tumors, 2) poor from good survival, and 3) prostate cancer in African-Americans from prostate cancer in Caucasians. We will also test the hypothesis that a high IGF-1 bioavailability, defined by high IGF-1 and low IGFBP3 blood concentrations, promotes prostate cancer by activating the Akt pathway in prostate tissue. We will measure plasma IGF-1 and IGFBP3 concentrations and correlate IGF-1 bioavailability with tissue markers of Akt activation, such as phosphorylated Akt and Erk1/2, apoptotic index, VEGF expression, and tumor microvessel density. The same research is currently being conducted in the aforementioned breast cancer study. Specific aims 1) Genetic susceptibility in nonhereditary prostate cancer is caused by allele variant genes that modulate inflammation, hormone-stimulated survival and proliferation of mutant cells, DNA repair capacity, and tumor angiogenesis. The susceptibility will depend on race and is modulated by gene-environment interactions. 2) The molecular signature of primary prostate tumors is different among African-American men and Caucasian men. The gene expression profile of African-Americans is associated with an early onset of the disease, a more rapid cancer progression, and poor survival. 3) A high IGF-1 blood concentration modulates gene expression in primary tumors. The molecular profile is associated with disease progression and poor survival. 4) A diet high in allium vegetables modulates gene expression in primary tumors. The molecular profile correlates with good survival. 5) A high IGF-1 bioavailability promotes cancer progression by activating the Akt pathway in the prostate. IGF-1 plasma concentrations, categorized in quartiles, correlate with tissue markers such as phosphorylated Akt, reduced apoptosis, and increased VEGF expression. 6) A diet high in allium vegetables inhibits the IGF-1 pathway.